New paper below. Full text is available. It is a lengthy paper, so I have included only a few extracts. Note: AR = Androgen Receptor.
I knew I would like the paper when I read that testosterone [T] had a "biphasic" effect on PCa. The word appears 19 times. I came across that claim 13 years ago, & I don't recall having seen the term since.
I don't think that T should be considered without also looking at estradiol [E2]. Men with the metabolic syndrome typically have increased visceral fat (which secretes E2) & lower T production. Even in the absence of MetS, the aging man suffers a relentless reduction of T. The E2:T ratio has been found to have significance elsewhere, but E2 is largely ignored in PCa. My feeling is that E2:T is important, in that when E2 is dominant, T is growth-permissive. This doesn't normally happen when T is dominant.
The paper refers to some old studies:
[2] (1967) Yes, fifty years ago!
"Twenty-six men in whom the diagnosis of prostatic carcinoma had been established recently and ten men with prostatic carcinoma in relapse after orchiectomy were administered testosterone propionate. Of the measures of tumor activity that were made the only objective alteration was in the serum acid phosphatase; however, in both groups of patients the response to testosterone was extremely variable. None of the ten men in relapse experienced complete objective remission although one man, who was preterminal, developed a remarkable subjective and partial objective remission that lasted nearly a year. Another patient received testosterone for 128 days and experienced only enlargement of the primary tumor. The authors conclude that the response to exogenous testosterone is variable and unpredictable and in certain patients in relapse may be of appreciable palliative value."
[3] (1982)
"Among 52 patients with metastatic adenocarcinoma of the prostate who were treated with exogenous testosterone, 45 (87%) experienced unfavorable subjective and/or objective responses. These unfavorable responses were elicited more frequently and after shorter treatment periods in patients in symptomatic relapse following endocrine therapy than in untreated patients or patients in remission following endocrine therapy. Serious morbidity or mortality, seemingly due to the testosterone administration, occurred in eight cases (15%). It is not known if the action of chemotherapeutic agents will be enhanced by concurrent testosterone therapy but any such investigation should be undertaken with extreme caution."
[4] (2009) "Testosterone therapy in castrate-resistant prostate cancer: a possible new approach."
...
"In contrast, abundant data from preclinical models have reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T concentrations proliferation is induced, but at higher, supraphysiological T (SPT) concentrations, proliferation is suppressed and in some instances apoptotic programs are engaged. Though often considered to be an in vitro phenomenon, recent proof of principle trials using SPT therapy—two in men with CRPC and one in hormone sensitive PCa produced promising results, showing radiographic response rates of ~50% in men with CRPC, and favorable prostate specific antigen (PSA) responses in those with hormone naïve PCa"
"Interestingly, despite his clear demonstration that androgens were a critical driver of PCa progression, Huggins himself proposed that both hormonal deprivation and hormonal excess (which he termed hormonal interference) might be used for therapeutic benefit" [5] (1965)
"A number of case reports and small series were published between 1950 and 1980. While demonstrating some evidence of clinical benefit, these studies also showed adverse effects of T administration, though the doses were generally low, ranging from 25 mg–100 mg daily. In a series of three patients, two experienced temporary symptomatic benefit. In a series of 10 men with CRPC treated with 100 mg T propionate 3 times weekly, one individual, near death at the time of treatment initiation, experienced an objective response lasting approximately 1 year, although five patients had subjective and objective evidence of deterioration including pain and pathologic fracture. Two case reports also detail responses to T therapy, one patient with progression despite orchiectomy and hypophysectomy who responded to T with a decrease in serum acid phosphatase and symptomatic improvement, and more recent patient with CRPC treated with T gel replacement with a sustained PSA response lasting for nearly a year."
"Importantly, simply discontinuing ADT and allowing androgen recovery to a eugonadal state does not appear to enhance survival; studies of intermittent androgen suppression in metastatic disease, which also allows gradual T recovery to physiological levels, demonstrated a trend toward inferior survival compared to continuous ADT. In this regard castration resistant VCaP cells treated with sequentially higher T doses had less significant apoptotic responses to androgen withdrawal than those seen in VCaP cells exposed to a single high T “boost”."
...
"Studies of Bipolar Androgen Therapy (BAT)
"In contrast to ... studies in which T was administered in continuous manner, the group of Denmeade and Isaacs has pioneered an approach termed Bipolar Androgen Therapy (BAT). Overexpression of AR is one of the most common molecular hallmarks of CRPC, and it was hypothesized that by rapidly cycling T levels between the supraphysiological (~1500 ng/dL) and near-castrate (~150 ng/dL) range, adaptive changes in AR expression would be blunted, thereby delaying the emergence of resistance. Data from these investigators has also suggested that AR becomes critically involved in the DNA replication licensing required for PCa cell proliferation. As discussed more fully below, increased ligand may over-stabilize AR on DNA, preventing its degradation and inhibits DNA relicensing, resulting in cell death in the subsequent cycle.
"Schweizer et al. reported the first clinical experience with this approach: 16 men with asymptomatic metastatic CRPC were treated with 400 mg of T intramuscularly (IM) monthly. Notably, 2 days after T administration, serum T levels exceeded 1500 ng/dL (~50 nM) and fell to <200 ng/dL at the end of each 28 day cycle. PSA declines (≥50%) were observed in nearly one-third of patients, radiographic responses were observed in 50% of men, and four continued on treatment for ≥1 year. At progression, ADT or AR inhibitory therapy produced responses in 100% of men, suggesting that BAT may restore sensitivity to ADT. Importantly, no patient developed worsening pain due to PCa, nor were there any other skeletal events or evidence of worsening urinary obstruction.
"In a follow up study recently reported by Teply et al, men with CRPC who had progressed on ENZ went on to receive BAT (n = 30). This study documented similar activity in response to BAT, with 9 of 30 (30%) men achieving a ≥50% decline in PSA from baseline and 50% of patients achieving an objective radiographic response. Twenty-nine patients progressed on BAT and went on to be re-challenged with ENZ. Fifteen of 29 (52%) had a PSA decline ≥50%, however, there were no objective radiographic responses and time to progression was generally short following ENZ re-challenge.
"In another study in hormone naive patients, 29 men with low metastatic burden or biochemically recurrent disease who achieved PSA < 4 ng/dL after 6 months of ADT were treated with alternating 3 month cycles of BAT (given as IM injections of 400 mg T cypionate or enanthate on days 1, 29 or 57), followed by 3 months of ADT alone. The primary endpoint was the percent of patients with a PSA < 4 ng/dL after two rounds of BAT-ADT (i.e., following the 18-month treatment period). Serum androgen levels were not reported. Three of 29 patients were taken off study prior to completing two cycles due to concerns for early progression. However, the 26 patients that completed the study as designed achieved a PSA below their pre-treatment baseline, with 17/29 (59%) achieving the primary endpoint of PSA < 4 ng/dL after 18 months, including three patients who had an undetectable PSA (<0.2 ng/mL) at the18-month time point. Of 10 men with measurable disease, four complete and four partial responses were observed. Notably, five of seven patients who did progress to CRPC by the end of the study responded to subsequent treatment with anti-androgen, again suggesting that BAT may restore sensitivity to ADT Treatment was associated with favorable improvement in QoL, although QoL diminished over the course of each cycle of BAT, presumably due to T levels falling below the normal range.
"BAT is currently being tested in a large (n = 180) randomized trial (NCT02286921; TRANSFORMER) in asymptomatic mCRPC patients who have failed on abiraterone. In this study, BAT is being compared with ENZ with a primary end point of progression-free survival (PFS). While the more substantive clinical benefit observed in the studies of BAT vs. other contemporary and historical studies of androgen treatment may reflect the bipolar dosing strategy, it is likely that it also is related to the fact that these are the only studies in which supraphysiologic androgens have been achieved. Importantly, the relative dearth of patients experiencing clinical deterioration on T treatment compared to historical studies highlights the importance of patient selection, which, in modern studies, was limited to asymptomatic patients with limited metastatic disease."
...
"A further consideration which merits discussion is the potential for aromatase-mediated conversion of exogenous T to E2. PCa cells can variably express one or both of ER-alpha (which can promote PCa proliferation) and ER-beta (which can inhibit PCa proliferation); thus the net effect of a possible increase in estrogen signaling may be adverse or beneficial depending on the relative level of each. Whether this is a clinically relevant concern is unclear, as the extent to which T undergoes intra-tumoral conversion to E2 in men treated with SPT is unknown. However, studies testing the combination of T with an aromatase inhibitor (either upfront or at evidence of disease progression) would be informative."
-Patrick
[1] mdpi.com/2072-6694/9/12/166...
[2] onlinelibrary.wiley.com/doi...
[3] onlinelibrary.wiley.com/doi...
